 Center
for Cancer Research
Bldg 149, 7th floor
13th Street
Charlestown, MA 02129
haber@helix.mgh.harvard.edu
617-726-7805
Publications
Lab Members |
Major Research Interests:
- Molecular Genetics Underlying Targeted Cancer Therapeutics
- Characterization of the Wilms Tumor Suppressor Genes WT1 and WTX
- Genetic Predisposition to Breast Cancer
Our laboratory is interested in the genetics of cancer, with primary emphasis on the characterization of tumor suppressor genes implicated in breast cancer and Wilms tumor, and the identification of somatic mutations linked to drug susceptibility in lung cancer.
Molecular Genetics Underlying Targeted Cancer Therapeutics
Activating mutations in the epidermal growth factor receptor (EGFR) were identified in our laboratory in the subset of non-small cell lung cancer (NSCLC) with dramatic responses to the tyrosine kinase inhibitor Gefitinib (Iressa®/Tarceva®). In collaboration with the Settleman laboratory, we have demonstrated that these mutations lead to ligand-dependent activation and enhanced inhibition by Gefitinib. NSCLC tumor cells harboring activating mutations of the EGFR kinase appear to be extraordinarily dependent upon survival signals that are differentially mediated by these mutant receptors, suggesting that oncogene addiction may underlie their exceptional sensitivity to kinase inhibitors. Studies of NSCLC cells with acquired resistance to Gefitinib have led to the characterization of a novel class of irreversible inhibitors of EGFR, which appear to circumvent such resistance and are now entering clinical trials. We have extended our modeling studies of targeted cancer therapies by demonstrating that a subset of gastric adenocarcinomas with amplification of the gene encoding the MET growth factor receptor are exquisitely sensitive to a specific kinase inhibitor, which is also now entering early phase clinical trials. Ongoing studies are aimed at defining genetic markers or responsiveness to targeted inhibitors. We have recently collaborated with the Toner laboratory to characterize a novel nanofluidic device capable of isolating circulating tumor cells (CTCs) from the blood of patients with known cancer. This “CTC-Chip” relies upon flow of blood through microposts coated with antibody to the epithelial marker EpCAM, to capture these CTCs with high efficiency (captured cells 50-500 cells/ml, purity 50-80%). We have shown that captured cell numbers are correlated with radiological evidence of tumor burden, and that the cells can be readily used to define molecular markers characteristic of the underlying malignancy. In addition to potential applications in early detection of cancer and as a prognostic marker, this approach offers an unprecedented opportunity to monitor tumor genotype over the course of treatment, which is key to the successful application of targeted cancer therapies.
Wilms Tumor
Wilms tumor is a pediatric kidney cancer that has been linked to inactivation of the WT1 gene, encoding a zinc finger transcription factor. Expression of WT1 is required for development of the kidney, gonads, and mesothelial tissues. Germline mutations in WT1 result in genetic predisposition to Wilms tumor; somatic mutations and a chimeric fusion with the EWS gene contribute to the development of Wilms and mesothelial tumors, respectively. Retrovirally-directed expression of WT1 in primary hematopoietic cells triggers lineage-specific differentiation. We have recently used comparative genomic hybridization to identify a novel Wilms tumor suppressor gene located on the X chromosome, which we have named WTX. Like WT1, WTX is expressed in early renal precursors and shows a tight developmental regulation of expression. Mutation in WTX are found in up to 30% of sporadic Wilms tumors, and appear to be mutually exclusive with those of WT1, pointing to distinct genetic etiologies. Remarkably, deletions and intragenic mutations targeting WTX display "one hit" inactivation, targeting the single X chromosome in males or the single active X chromosome in females. WTX is the first tumor suppressor identified on the X chromosome. Its functional properties are under study.
Genetic Predisposition to Breast Cancer
Genetic predisposition to breast cancer is associated with mutations in genes that mediate the cellular response to DNA damage, including p53, BRCA1, and BRCA2. We identified germline mutations in the checkpoint kinase CHK2 in cancer-prone families. The truncating mutation CHK2 1100delC is now known to be present in ~1% of the population and to constitute a low penetrance breast cancer allele. Ongoing studies are aimed at searching for additional genetic variants associated with susceptibility to breast and other cancers.
Selected Publications
Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nature Reviews Cancer. 7:169-81, 2007.
Haber DA, Settleman J. Cancer: drivers and passengers. Nature. 446:145-6, 2007.
Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, Kim JC, Feinberg AP, Gerald WL, Vargas SO, Chin L, Iafrate AJ, Bell DW, Haber DA. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 315: 642-5, 2007.
Diederichs S and Haber DA. Dual role for Argonaute proteins in microRNA processing and post-transcriptional regulation of microRNA expression. Cell, 2007 (in press).
Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, and Toner M. Microchip-based isolation of rare circulating epithelial cells in cancer patients. Nature, 2007 (in press).
Also see the Center for Cancer Risk Assessment
List of Publications for
Haber Laboratory
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